Enzymes primarily responsible for protein biosynthesis, such as the amino-acyl-tRNA synthetases, are not apt to be circumvented by other cellular mechanisms; thus, antimetabolites that are capable of species or tissue selective inhibition of these enzymes would be of great value to chemotherapy in general and to cancer chemotherapy in particular. Active-site-directed irreversible inhibitors provide an approach in the achievement of species and tissue selective inhibition of substrate identical enzymes not likely to be obtained with reversible inhibitors. Furthermore, properly designed analogs of an intermediate formed in an enzymic reaction should show intrinsic specificity for the target enzyme with little or no effect on other cellular enzymes; irreversible inhibitors that take advantage of this feature should inherently possess intra-cellular specificity for the target enzyme, and inter-cellular specificity for substrate identical enzymes. We have also been developing methods for purification of the glucocorticoid receptor. We propose to characterize it and investigate its biochemical mechanism.